Extraperitoneal v Intraperitoneal Robotic Prostatectomy: Analysis of Operative Outcomes

Background and Purpose: Robotic prostatectomy can be performed either via an extra- or intraperitoneal approach. The extraperitoneal approach has advantages similar to those of an extraperitoneal open radical prostatectomy, but the potential disadvantages of a small working space. We report our experience using both approaches. Methods: From July 2003 to June 2004, 55 patients underwent a robot-assisted laparoscopic prostatectomy. During the first 6 months, 21 prostatectomies were performed using an intraperitoneal approach (group 1); 34 were performed using an extraperitoneal approach (group 2) during the next 6 months. Clinicopathologic parameters and perioperative complications were compared in both groups. All patients were categorized as intent-to-treat analysis. Results: Median surgery time was significantly shorter in the extraperitoneal compared with the intraperitoneal approach (3 hours and 34 minutes v 4 hours and 1 minute, respectively, P = 0.017). This was because of the shorter time interval between the skin incision and incision of the endopelvic fascia in the extraperitoneal v the intraperitoneal approach (55 minutes v 74 minutes, respectively, P < 0.0001). There was no significant difference in terms of patient age, clinical and pathologic stage, length of hospital stay, and perioperative complications between the two approaches. Conclusion: Extraperitoneal robot-assisted laparoscopic prostatectomy offers a similar clinical outcome as the intraperitoneal approach. However, the extraperitoneal approach avoids potential bowel injury or complications related to an intraperitoneal urine leak.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63120/1/end.2007.9872.pd

Five-year survival after surgical treatment for kidney cancer

BACKGROUND. Kidney cancer's rising incidence is largely attributable to the increased detection of small renal masses. Although surgery rates have paralleled this incidence trend, mortality continues to rise, calling into question the necessity of surgery for all patients with renal masses. Using a population-based cohort, a competing risk analysis was performed to estimate patient survival after surgery for kidney cancer, as a function of patient age and tumor size at diagnosis. METHODS. With data from the Surveillance, Epidemiology, and End Results Program (1983–2002), a cohort was assembled of 26,618 patients with surgically treated, local-regional kidney cancer. Patients were sorted into 20 age-tumor size categories and the numbers of patients that were alive, dead from kidney cancer, and dead from other causes were tabulated. Poisson regression models were fitted to obtain estimates of cancer-specific and competing-cause mortality. RESULTS. Age-specific kidney cancer mortality was stable across all size strata but varied inversely with tumor size. Patients with the smallest tumors enjoyed the lowest cancer-specific mortality (5% for masses ≤4 cm). Competing-cause mortality rose with increasing patient age. The estimated 5-year competing-cause mortality for elderly subjects (≥70 years) was 28.2% (95% confidence interval [CI]: 25.9%–30.8%), irrespective of tumor size. CONCLUSIONS. Despite surgical therapy, competing-cause mortality for patients with renal masses rises with increasing patient age. After 5 years, one-third of elderly patients (≥70 years) will die from other causes, suggesting the need for prospective studies to evaluate the role of active surveillance as an initial therapeutic approach for some small renal masses. Cancer 2007. © 2007 American Cancer Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55991/1/22600_ftp.pd

Comparison of joint modeling and landmarking for dynamic prediction under an illness‐death model

Dynamic prediction incorporates time‐dependent marker information accrued during follow‐up to improve personalized survival prediction probabilities. At any follow‐up, or “landmark”, time, the residual time distribution for an individual, conditional on their updated marker values, can be used to produce a dynamic prediction. To satisfy a consistency condition that links dynamic predictions at different time points, the residual time distribution must follow from a prediction function that models the joint distribution of the marker process and time to failure, such as a joint model. To circumvent the assumptions and computational burden associated with a joint model, approximate methods for dynamic prediction have been proposed. One such method is landmarking, which fits a Cox model at a sequence of landmark times, and thus is not a comprehensive probability model of the marker process and the event time. Considering an illness‐death model, we derive the residual time distribution and demonstrate that the structure of the Cox model baseline hazard and covariate effects under the landmarking approach do not have simple form. We suggest some extensions of the landmark Cox model that should provide a better approximation. We compare the performance of the landmark models with joint models using simulation studies and cognitive aging data from the PAQUID study. We examine the predicted probabilities produced under both methods using data from a prostate cancer study, where metastatic clinical failure is a time‐dependent covariate for predicting death following radiation therapy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140034/1/bimj1778.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140034/2/bimj1778_am.pd

A pooled long-term follow-up after radiotherapy for prostate cancer with and without a rectal hydrogel spacer: Impact of hydrogel on decline in sexual quality of life

PURPOSE: The purpose of this study was to analyze the impact of prostate rectal spacers on sexual quality of life (QOL) following external beam radiation therapy (RT). METHODS AND MATERIALS: Patient- reported QOL was evaluated using the Expanded Prostate Cancer Index Composite (EPIC). Patients were pooled from two sources: a randomized controlled trial and a non-randomized cohort of patients from a single institution. Both cohorts used the same spacing product and QOL instrument. Analysis was limited to those with good baseline pre-treatment sexual QOL (EPIC \u3e/= 60). Differences in QOL summary score and individual items were assessed compared with baseline and between treatment arms. RESULTS: A total of 128 men had good baseline sexual function and were evaluated (64% with spacer and 36% without) with QOL data available for median 33 months (range: 2.5-69.4 months). Men without spacer were more likely to have declines in sexual function ( CONCLUSION: In this pooled analysis of QOL after prostate RT, the utilization of a hydrogel spacer was associated with better sexual QOL, less men with measurable declines in sexual QOL, and higher rates of adequate erectile function

IL‐4 induces proliferation in prostate cancer PC3 cells under nutrient‐depletion stress through the activation of the JNK‐pathway and survivin up‐regulation

Interleukin (IL)‐4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumor microenvironment of cancer patients where it correlates with the grade of malignancy. The direct effect of IL‐4 on cancer cells has been associated with increased cell survival; however, its role in cancer cell proliferation and related mechanisms is still unclear. Here it was shown that in a nutrient‐depleted environment, IL‐4 induces proliferation in prostate cancer PC3 cells. In these cells, under nutrient‐depletion stress, IL‐4 activates mitogen‐activated protein kinases (MAPKs), including Erk, p38, and JNK. Using MAP‐signaling‐specific inhibitors, it was shown that IL‐4‐induced proliferation is mediated by JNK activation. In fact, JNK‐inhibitor‐V (JNKi‐V) stunted IL‐4‐mediated cell proliferation. Furthermore, it was found that IL‐4 induces survivin up‐regulation in nutrient‐depleted cancer cells. Using survivin‐short‐hairpin‐RNAs (shRNAs), it was demonstrated that in this milieu survivin expression above a threshold limit is critical to the mechanism of IL‐4‐mediated proliferation. In addition, the significance of survivin up‐regulation in a stressed environment was assessed in prostate cancer mouse xenografts. It was found that survivin knockdown decreases tumor progression in correlation with cancer cell proliferation. Furthermore, under nutrient depletion stress, IL ‐4 could induce proliferation in cancer cells from multiple origins: MDA‐MB‐231 (breast), A253 (head and neck), and SKOV‐3 (ovarian). Overall, these findings suggest that in a tumor microenvironment under stress conditions, IL‐4 triggers a simultaneous activation of the JNK‐pathway and the up‐regulation of survivin turning on a cancer proliferation mechanism. J. Cell. Biochem. 113: 1569–1580, 2012. © 2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90542/1/24025_ftp.pd

Clinical Correlates of Benefit From Radium‐223 Therapy in Metastatic Castration Resistant Prostate Cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136309/1/pros23286.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136309/2/pros23286_am.pd

Characterization of glycine-N-acyltransferase like 1 (GLYATL1) in prostate cancer

BackgroundRecent microarray and sequencing studies of prostate cancer showed multiple molecular alterations during cancer progression. It is critical to evaluate these molecular changes to identify new biomarkers and targets. We performed analysis of glycine-N-acyltransferase like 1 (GLYATL1) expression in various stages of prostate cancer in this study and evaluated the regulation of GLYATL1 by androgen.MethodWe performed in silico analysis of cancer gene expression profiling and transcriptome sequencing to evaluate GLYATL1 expression in prostate cancer. Furthermore, we performed immunohistochemistry using specific GLYATL1 antibody using high-density prostate cancer tissue microarray containing primary and metastatic prostate cancer. We also tested the regulation of GLYATL1 expression by androgen and ETS transcription factor ETV1. In addition, we performed RNA-sequencing of GLYATL1 modulated prostate cancer cells to evaluate the gene expression and changes in molecular pathways.ResultsOur in silico analysis of cancer gene expression profiling and transcriptome sequencing we revealed an overexpression of GLYATL1 in primary prostate cancer. Confirming these findings by immunohistochemistry, we show that GLYATL1 is overexpressed in primary prostate cancer compared with metastatic prostate cancer and benign prostatic tissue. Low-grade cancers had higher GLYATL1 expression compared to high-grade prostate tumors. Our studies showed that GLYATL1 is upregulated upon androgen treatment in LNCaP prostate cancer cells which harbors ETV1 gene rearrangement. Furthermore, ETV1 knockdown in LNCaP cells showed downregulation of GLYATL1 suggesting potential regulation of GLYATL1 by ETS transcription factor ETV1. Transcriptome sequencing using the GLYATL1 knockdown prostate cancer cell lines LNCaP showed regulation of multiple metabolic pathways.ConclusionsIn summary, our study characterizes the expression of GLYATL1 in prostate cancer and explores the regulation of its regulation in prostate cancer showing role for androgen and ETS transcription factor ETV1. Future studies are needed to decipher the biological significance of these findings.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151252/1/pros23887.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151252/2/pros23887_am.pd

Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer

Cell plasticity regulated by the balance between the mesenchymal to epithelial transition (MET) and the opposite program, EMT, is critical in the metastatic cascade. Several transcription factors (TFs) are known to regulate EMT, though the mechanisms of MET remain unclear. We demonstrate a novel function of two TFs, OVOL1 and OVOL2, as critical inducers of MET in human cancers. Our findings indicate that the OVOL-TFs control MET through a regulatory feedback loop with EMT-inducing TF ZEB1, and the regulation of mRNA splicing by inducing Epithelial Splicing Regulatory Protein 1 (ESRP1). Using mouse prostate tumor models we show that expression of OVOL-TFs in mesenchymal prostate cancer cells attenuates their metastatic potential. The role of OVOL-TFs as inducers of MET is further supported by expression analyses in 917 cancer cell lines, suggesting their role as crucial regulators of epithelial-mesenchymal cell plasticity in cancer

Change in Markers of Bone Metabolism with Chemotherapy for Advanced Prostate Cancer: Interleukin-6 Response Is a Potential Early Indicator of Response to Therapy

Men with androgen-independent prostate cancer (AIPC) frequently have bone metastasis. The effects of chemotherapy on markers of bone metabolism have not been well characterized. We conducted a prospective study of patients with AIPC randomized in the first cycle to receive either docetaxel/estramustine or zoledronic acid, a bisphosphonate, to inhibit osteoclastic activity. Here we report the effects of therapy on markers of bone metabolism in these patients following the first cycle of therapy. Serum levels of several indices of bone remodeling were evaluated using commercial enzyme-linked immunosorbent assays. Changes in markers of bone metabolism were compared in patients receiving initial chemotherapy versus bisphosphonate. There was no significant difference in median change in any of the measured bone markers in patients given zoledronic acid when compared to chemotherapy. When comparing responders to nonresponders, overall interleukin-6 (IL-6) decreased by 35% in prostate-specific antigen responders; whereas, IL-6 levels increased by 76% in nonresponders (p = 0.03). Elevated IL-6 levels and reductions in IL-6 levels early in treatment may reflect ultimate clinical response to docetaxel-based regimens.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78145/1/jir.2008.0024.pd

Double‐blind, randomized, phase 2 trial of maintenance sunitinib versus placebo after response to chemotherapy in patients with advanced urothelial carcinoma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106126/1/cncr28477.pd